Abstract
This study aimed to report cancer incidence and mortality in a Brazilian human immunodeficiency virus (HIV) cohort of 31 years duration and compare cancer deaths with deaths due to noncancer causes. We also investigated risk factors for the development of acquired immunodeficiency syndrome (AIDS)-defining and non-AIDS-defining cancers. We searched for any information related to the diagnosis of cancer in a period ranging from 1989 to 2020. We also collected data on sociodemographic and clinical information and risk factors. Statistical analysis included parametric and nonparametric tests and the building of survival curves. We used the statistical software GraphPad software (version 9) and STATA software (version 14) for the elaboration of statistics. Fifty-five new cases of cancer occurred in a total of 677 HIV patients included in our cohort over 31 years, an incidence of 8.12%. The most important risk factors associated with cancer were smoking (p = 0.03), infection with oncoviruses like human papillomavirus (p < 0.001), and hepatitis C (p = 0.04). Eleven patients (1.6%) died from cancer. The most frequent diagnoses of fatal cancer were liver cancer and lymphoma (three cases each). The mean follow-up time of patients dying from cancer was 14 years; patients dying from noncancer causes were 24 (3.55%), and their mean follow-up time was 11 years. We had low overall mortality in our cohort of HIV patients (5.2%), mostly due to noncancer causes, which may be due to the fact that most of our patients begin follow-up asymptomatic. Cancer deaths were 31.4% of all deaths; half of those cancers were AIDS-defining.
Introduction
Untreated human immunodeficiency virus (HIV) infection may cause severe changes in the immune system, making patients susceptible to opportunistic diseases and some specific cancers, constituting the acquired immunodeficiency syndrome (AIDS).1 , 2 Despite the advances of the last decades, with increased survival and decreased opportunistic infections in people living with HIV/AIDS (PLWHA) with the introduction of antiretroviral therapy, new challenges are currently imposed.3
Several studies place priority on the prevention of cognitive alterations, renal and bone alterations, among other comorbidities, among which several cancers that became the focus of concern for these patients; mortality from malignant tumors reached 15% in HIV carriers worldwide.4 Thus, the early diagnosis of cancers is necessary to reduce these cancer rates in people living with HIV (PLHIV).4 According to data from the International Agency for Research on Cancer, the estimated number of new cancer cases worldwide in the year 2020 was 19,292,789 individuals, and for 2040, more than 30 thousand new cases are expected.5
For Brazil, according to the National Institute of Cancer, the estimates of new cases of the three more frequent cancers in 2020, in men, were 65,840 (29.2%) cases of prostate cancer, following of colon/rectum, and in the (8%) in respiratory tract, including lung cancer; for women, the estimates were 66,280 (29.7%) new cases of breast cancer, 20,470 (9.2%) of colon and rectum cancers, and 16,710 (7.5%) of cervix cancer.6 A Brazilian outpatient study demonstrates the importance of screening and prevention: findings of the study included an incidence of 30 cases of cancer, 16 AIDS-defining, and 14 non-AIDS-defining. The authors stressed the higher case-fatality rate of cancer in HIV patients.7 In an international study, including Brazilian patients, among 15,869 patients, 783 had an eligible cancer diagnosis, 82% were male, and median age at cancer diagnosis was 39 years, 36.5% from Brazil. A total of 564 AIDS-defining cancers (ADCs), compared to 219 nondefining cancer (NADC), were diagnosed from 2000 to 2015. The survival rate is 81% vs 79%, but lower survival at 5 years is 60% vs 69%.8
It is possible that HIV impairs the natural killer function and/or release of cytokines, such as IFN, which may induce more susceptibility to appearance of cancer, regardless of successful treatment with antiretroviral therapies (ARTs).9 , 10 In fact, previous studies noted that low CD4 + T cell counts and nadir at the beginning of antiretroviral therapy are associated with an increased risk of all types of cancer.11 ADCs are associated with immunosuppression and decreased HIV-related immune surveillance.12 Despite cancer being an important cause of mortality, there is a lack of data regarding Brazil, especially in the epicenter of the HIV/AIDS pandemic. Thus, in this study, we assess the incidence, some associated risk factors, and survival among PLHIV in an outpatient service in São Paulo, over the last 31 years.
Methods
This is an observational study of the cancer incidence and mortality in 677 patients HIV-1 followed at outpatient service from Hospital of Clinics, São Paulo University Medical School, by 31 years (from 1989 to 2020). Information about these patients was searched in medical records and databases. We included all our adult HIV patients with 18 years of age or more.
Exclusion criteria were incomplete information and patients whose date of HIV and/or cancer diagnoses were unknown. In addition, we also collected sociodemographic and clinical information, the latter including a previous diagnosis of AIDS, lowest and current CD4+ cells counts, highest and current HIV viral load, and risk factors for cancer, such as alcohol consumption, history of smoking status, sedentary lifestyle, excess weight, ADCs (Hodgkin’s disease), and non-ADCs (pulmonary cancer), for example. The cancer diagnosis was confirmed by anatomopathological examination from specimens obtained by biopsy and coded according to the International Classification of Diseases and Health-Related Problems, 10th edition (ICD-10). We also searched for evidence of current or previous infection with viruses associated with cancer, such as human T-lymphotropic virus type 1 (HTLV-1, adult T leukemia/Lymphoma), Epstein Barr virus (EBV; head/neck carcinoma), hepatitis C virus (HCV; hepatocellular carcinoma), and human papillomavirus (HPV, invasive cervical cancer in women, for example) related cancer. We also collected information on the current vital status of all patients in the cohort and the causes of death of the deceased.
Statistical analysis
We used descriptive statistics to compare baseline characteristics between ADCs and non-AIDS-defining. Quantitative variables were calculated as means and standard deviations (SDs) and median for numerical variables. For dichotomous and categorical variables, we reported the relative frequency. We used the chi-square test, the unpaired t test, and univariate and multivariate logistic regressions. Statistical analysis included parametric and nonparametric tests, and the building of survival curves indicates statistical significance p < 0.05. We obtained Kaplan Meier survival estimates; the log-rank test was used for comparing survival curves. Statistical analysis was performed with the aid of GraphPad software (version 9) and STATA software (version 14).
Ethical considerations
The study project was approved by the Research and Ethics Committee of the Institute of Tropical Medicine of the University of São Paulo under the number CPE-IMT 000364 and by the Ethics Committee of the Faculty of Medicine of the University of São Paulo (CAPPesq) and registered under Platform Brasil, number 3,617,699 and CAAE: 21165718.1.0000.0068.
Results
In this study, 677 HIV/AIDS patients were included from 1989 to 2020; from this total, 381 (56.3%) are currently active in the clinic. Fifty-five patients were diagnosed with cancer in 31 years of outpatient follow-up (Fig. 1). Some main demographic and clinical characteristics of cancer patients are as follows: 27 (49.10%) patients were 40–59 years old, 35 (63.64%) patients were male, 42 (76.36%) patients were white, and 36 (65.45%) had 10–12 years of schooling. The mean age at the time of cancer diagnosis in patients was 43.87 years. Laboratory tests results obtained at cancer diagnosis included CD4+ cell count of <350 cells/mm³ (n = 20; 36.36%) versus 29 with ≥350 (52.73%); the mean CD4+ cell count was 467, median viral load was 12,700 copies for 24 patients, whereas 31 had undetectable viral load; nadir CD4, AIDS vs non-AIDS, and some results of laboratory tests that could influence the onset of cancer are displayed in Table 1. Five patients were currently off ART. Mean duration of antiretroviral therapy was 8.86 years for patients without cancer and 10.17 years for cancer patients (p = 0.09).
Algorithm used among patients living with HIV in the ADEE3002 cohort.
Demographic and clinical characteristics of 622 HIV-infected patients and 55 who progressed to cancer (n = 677 patients)
*Nadir: The lowest CD4+ T-cell count according to the patient’s lifetime. Test used: chi-square test.
The risk factors evaluated in the study were smoking status (p = 0.03), alcohol consumption, sedentary lifestyle, high body mass index, and infection with main oncogene viruses, such as HPV (p < 0.001) and HCV (p = 0.034), as shown in Table 2. The most frequent ADC was cervix uteri cancer (10 of 15, 66.6%); 15 (27.3%) were AIDS-defining and 40 (72.7%) were non-AIDS-defining (Tables 3–5).
Risk factors associated with cancer in HIV patients in the Brazilian cohort
Note. *indicate the significance value p. Test used: Chi-square test.
Univariate analysis of covariates associated with cancer outcome
Multivariate analysis of covariates associated with cancers outcome
Distribution of AIDS-defining cancers and non-AIDS-defining cancers in people living with HIV with ICD-10 category
Eight patients presented recurrence of the cancer, and one of the patients with non-Hodgkin’s lymphoma, presented recurrence of the cancer (secondary neoplasms: brain tumor (1); peritoneal carcinomatosis (1); recurrence of non-Hodgkin’s lymphoma (1); anal cancer (2); anal epidermoid carcinoma (1); basal cell carcinoma (1); and cervix cancer (1)).
There were 11 deaths from cancer over the 31 years of the cohort, the most frequent being liver cancer (Table 6). Other deaths from various causes occurred in the cohort, with a total of 24. The most frequent cause of noncancer death was tuberculosis, with 5 deaths (20%) (Table 7). So, among our 677 patients, 11 died from cancer (1.6%) and 24 from other causes (3.55%), during our 31-year period of follow-up. The median survival, measured from the first HIV positive serology, was 14 years for patients who died from cancer and 11 years for those dying from other causes. The estimated probability of having HIV and cancer and being alive after 14 years of the first positive HIV test was 50% (Table 8).
Causes of cancer mortality in a cohort of people living with HIV in the ADEE-3002 outpatient clinic
Causes of mortality from noncancer causes in a cohort of PLHIV in the ADEE-3002 outpatient clinic
Tuberculosis includes: pulmonary (3); disseminated tuberculosis (1); tuberculosis respiratory failure (1).
No data (1).
Types of cancers diagnosed in the pre- and post-ART
Discussion
While it is important to know the number of PLHIV who are developing cancer, it is also necessary to understand the risk factors and causes of death in the HIV population. In previous studies, cancer was responsible for less than 1% of deaths during the pre-ART era and, currently, represents almost 15% of all deaths among PLHIV.13 One possible reason, raised in a previous study, implicated the increase in life expectancy of HIV/AIDS patients, brought about by efficient antiretroviral therapy. In that study, males represented 60% of the patients, and the median age was 44 years.7 In the present study, males were even more frequent, maybe due to delay in seeking health care; the mean age of cancer patients was 43.87 years. Our cohort is invented mainly of men who have sex with men (70%), who have an enhanced risk for HPV infection.14 , 15 Furthermore, these data may have some impact because no information of clinical outcome, such as death information, was captured, and if any patients were lost to follow-up. The average follow-up time in the cohort was 52 months. Generally, 11% of all participants lost follow-up during the study period. Mortality among cohort participants lost to follow-up decreased the estimated life expectancy and increased the estimated mortality rate, as expected.16 Given that the T-cell CD4+ counts <200 (22%) of patients, reporting an overall mortality rate of 5.2%. It is possible to infer these findings, again, due to the loss of follow-up and median survival.
The most frequent risk factors associated with cancer are smoking status, alcohol abuse, sedentary lifestyle, obesity, and the presence of coinfection with oncogene viruses, including HPV and HCV.17–19 In China, in 2017, the prevalence of cancer risk factors in a systematic review and meta-analysis revealed that smoking status was present in 41.1% and alcohol in 30.3% of cancer cases, pointing to the decisive contribution of alcohol abuse and heavy smoking status to the incidence of cancer.20 Other important risk factors were excess weight and obesity (BMI> 24.9 kg/m2), which found in 24% of PLHIV in that same study.20 Several studies show that a sedentary lifestyle has a strong association with the risk of cancer.21–27 In the present study, the most important risk factors were a BMI >24.9 and smoking status. Viral hepatitis and alcohol abuse are the main risk factors for the development of hepatocellular cancer.28 , 29 Immunization with the HPV vaccine is recommended by the Brazilian Ministry of Health for men and women living with HIV, besides being included in the regular immunization schedule of all children.30
In the present study, we found oncoviruses, such as HPV and HCV, in our patients with cancer, implicating a higher risk of death. This is due to the development of hepatocellular carcinoma, patients who consume alcohol and/or are coinfected with HCV. Some studies have highlighted a significant association between the risk of non-ADCs and the nadir of CD4 + T lymphocytes.31–33 The lower counts of CD4+ T lymphocytes and the development of non-ADCs with the early introduction of antiretroviral therapy may have a protective effect on cancers.31–33 This study demonstrated the importance of a nadir CD4+ level (<350 cells/mm³) in the risk of both AIDS-defining and non ADCs. In contrast, in a multinational study in Latin America, mortality increased with detectable viral load, age, and time between HIV and cancer diagnoses. In general, ADC remains the most frequent cancers in the region. Longer-term survival was lower after diagnosis of NADC than for ADC, which may be due to factors unrelated to HIV.8
The 5-year survival of HIV patients with cancer, compared with that of non-HIV patients, was reported in a study from Italy; only 12 percent of PLHIV survived, as compared with a 66 percent survival for non-HIV patients.34 For comparison, in a Brazilian study, 49.6% of HIV patients survived for 5 years, whereas 72.7% of non-HIV patients survived for the same time. For almost all cancer types and/or location, HIV patients had worse prognosis.35 In the current study, survival of PLHIV with cancer was higher than that of HIV patients with other diseases. The most frequent single cause of cancer death was hepatocellular carcinoma (27.3%). From the 35 total deaths in our study, 11 were due to cancer and 24 to other causes, reflecting the importance of noncancer causes of death in our study.
Conclusion
In conclusion, smoking status, HPV, and HCV were the risk factors more strongly associated with cancers in this study. This demonstrates the importance of immunizing PLHIV with the HPV vaccine. Therefore, preventive strategies, such as identifying and treating HPV or HCV infection in the fastest possible way, both for women and men, may reduce the incidence of cancer in PLHIV. Besides, encouraging healthier lifestyles, such as quitting tobacco use, drinking little alcohol, reducing obesity, promoting physical activity, among others, can minimize the effects of unhealthy habits in the long fashion, contributing to longer survival and quality of life of persons living with HIV.
The presence of anal neoplasm (CID-10 C21) by HPV infection should be important to define as AIDS-event, as has done in cervical/uterine in women. This finding may indicate that anal neoplasm should be included as an opportunistic infection among PLHIV, regardless of gender. Thus, additional studies would be assessed to include HPV as an AIDS event among PLHIV in a long fashion.
Footnotes
Acknowledgments
We dedicate this work to all our patients over the last 31 years and to former medical residents, and we thank the volunteer’s Maria Olimpia Ribeiro Freitas and Maria Tereza de Figueiredo for more than 20 years of work in the Ambulatório de Imunodeficiências Secundárias do Hospital das Clínicas and Scholarship to BP from CAPES: 88887.464753/2019-00.